Download The Journal of Rheumatology Volume 37, no. 8 Tight Control

The Journal of Rheumatology
Volume 37, no. 8
Improving the Routine Management of Rheumatoid Arthritis: The Value of
Tight Control
PHILIP J. MEASE
J Rheumatol 2010;37;1570-1578
http://www.jrheum.org/content/37/8/1570
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The Journal of Rheumatology is a monthly international serial edited by Duncan A.
Gordon featuring research articles on clinical subjects from scientists working in
rheumatology and related fields.
Review
Improving the Routine Management of Rheumatoid
Arthritis: The Value of Tight Control
PHILIP J. MEASE
ABSTRACT. Evidence is mounting that adopting a tight control approach to the management of patients with
rheumatoid arthritis (RA) yields superior clinical outcomes including inhibition of progressive structural damage. While this approach has been successfully implemented in other chronic diseases, such
as diabetes, its use in RA is less straightforward as there is not a simple “gold standard” measure for
disease activity. A key component of the tight control approach is the availability of easily implemented and clinically relevant assessment measures of disease activity that allow physicians to monitor progress toward preset goals. This article summarizes the evidence from clinical trials demonstrating the benefits of achieving tight control and surveys the instruments available to assess patient
progress in a consistent manner. A case study clearly demonstrates the benefits of the tight control
approach in routine clinical practice. (First Release July 1 2010; J Rheumatol 2010;37:1570–8;
doi:10.3899/jrheum.091064)
Key Indexing Terms:
DISEASE MANAGEMENT
BIOLOGIC THERAPY PATIENT OUTCOMES ASSESSMENT
Rheumatoid arthritis (RA) is a chronic and generally progressive systemic autoimmune disease that affects
0.5%–1% of adults worldwide, being more prevalent in
women than in men, and in older people1. RA is characterized by chronic inflammation of the synovial membrane of
affected joints. Most patients also experience deterioration
of cartilage and bone over time, leading to pain, disability,
and premature mortality1. Despite considerable therapeutic
advances, many patients with RA experience active disease,
progressive joint damage and disability, and comorbidities,
including premature cardiovascular disease. No substantial
improvement in survival rates has been observed over the
last 40 years2, although this situation may have begun to
improve over the last decade, possibly due to changes in
clinical practice and the availability of the newer biologic
therapies3. Among possible reasons for the relative lack of
progress with regard to survival rates may be the infrequent
use, in routine clinical practice, of suitable measures of disease control that can be used to set treatment goals and to
monitor patients’ progress. While numerous research tools
— such as the American College of Rheumatology (ACR)
From Seattle Rheumatology Associates, Seattle, Washington, USA.
Support for third-party writing assistance for this report, furnished by
Neil Anderson, was provided by Genentech, Inc. and Biogen Idec.
P.J. Mease, MD.
Address correspondence to Dr. P.J. Mease, Seattle Rheumatology
Associates, 1101 Madison Street, Suite 1000, Seattle, WA 98104, USA.
E-mail: [email protected]
Full Release Article. For details see Reprints/Permissions at jrheum.org
Accepted for publication March 8, 2010.
core data set and the Disease Activity Score (DAS) — are
used in clinical trials, these complex instruments are unsuitable for busy rheumatology clinics. Consequently, treatment
is generally determined on an individual patient basis without reference to appropriate targets, a process that has been
likened to “giving treatment for a fever without a temperature, or rapid heart rate without a pulse”4.
Recent improvements in the treatment of RA have meant
that clinical remission is now a realistic target for many
patients. Indeed, it is now widely accepted that setting
remission as the goal of treatment is critical in order to prevent progressive joint damage. As a result of these developments, it is now essential that clinicians have an accurate,
reliable definition of remission and are able to accurately
measure low levels of disease activity.
The concept of “tight control” — treating patients to
specified targets with aggressive therapy if necessary — has
produced important benefits in conditions such as type I diabetes mellitus5. For example, the Diabetes Control and
Complications Trial showed that intensive treatment significantly reduced the risk of retinopathy progression and clinical neuropathy, and significantly lowered the risk of cardiovascular events versus standard treatment6.
In routine clinical practice, achieving tight control has 2
prerequisites. First, a validated quantitative assessment is
needed to facilitate continual monitoring of disease activity
over time. Second, assessments need to be quick and easy to
perform in routine clinical practice, and adaptable to multiple formats. Notably, tight-control studies in patients with
diabetes or hypertension have shown that improved out-
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comes can be achieved in well informed patients who understand the meaning of the parameters being investigated7,8.
This article examines recent clinical data demonstrating
the potential benefits of tight control for patients with RA,
and reviews some assessment tools that may be suitable for
implementing tight control. Finally, a case study illustrating
the difference tight control can make to individuals with RA
is presented.
Advantages of Tight Control: Evidence from Clinical
Trials
Several clinical trials have demonstrated the advantages of
tight control in patients with RA. Among the first was the
Finnish Rheumatoid Arthritis Combination Therapy trial,
which compared disease-modifying antirheumatic drug
(DMARD) combination therapy against DMARD
monotherapy in patients with early RA. This study was one
of the first to test whether the use of early aggressive combination DMARD therapy could alter the course of the disease by inducing long-lasting remission. Treatment aimed to
achieve or maintain clinical remission9, defined as meeting
American College of Rheumatology (ACR) remission criteria10. In the combination group, patients received sulfasalazine (SSZ), methotrexate (MTX), hydroxychloroquine, and prednisolone. Treatment was intensified by
increasing the doses of MTX and prednisolone at 3 months
if improvement in 2 of the 3 measures [swollen joint score;
tender joint score; and erythrocyte sedimentation rate (ESR)
or C-reactive protein (CRP)] was < 50%. In the monotherapy arm, patients initially received SSZ, the dose of which
was increased if clinically indicated. However, if there was
< 25% clinical improvement at 6 months, SSZ was replaced
with MTX. After 2 years, 37% of combination therapy
patients and 18% of monotherapy patients had clinical
remission, as defined by Pinals and colleagues11. Mean
improvements in swollen joint count and ESR were also
higher in patients receiving combination therapy than in
those receiving monotherapy, although levels of disease
activity as assessed by various clinical measures were similar in the 2 groups. Five-year followup results showed a
drop in clinical remission rates for combination therapy,
with 28% of patients achieving remission (22% for
monotherapy), although longterm retardation of joint damage continued12. Overall, this trial showed that early aggressive initial combination therapy using standard DMARD, in
the context of tight disease control, can lead to high clinical
remission rates and prevention of longterm joint damage.
The multicenter randomized BeSt (Behandel-Strategieën; “treatment strategies”) study assessed a number of
different treatment strategies in 508 patients with early
RA13. The significance of this study, however, lies with the
intensive monitoring specified in the protocol; patients were
allocated to 1 of 4 treatment arms, with treatment being
adjusted every 3 months to maintain a prespecified level of
disease activity (DAS ≤ 2.4). For all groups, the protocol
described a number of treatment steps for patients whose
medications failed. Group 1 (sequential monotherapy)
received MTX, the dose of which was increased if DAS was
> 2.4. Subsequent options included SSZ or leflunomide
monotherapy. Group 2 (step-up combination therapy) also
started with MTX. If response was inadequate after a dose
increase, SSZ was added, followed by hydroxychloroquine,
and then prednisone. Patients whose disease failed to
respond could be switched to other combinations including
MTX with infliximab. Group 3 (initial combination therapy
with prednisone) received MTX, SSZ, and prednisone; other
agents were added if response was inadequate. Group 4 (initial combination with infliximab) started with MTX and
infliximab; the dose of infliximab was increased if disease
failed to respond adequately. If patients still had a DAS >
2.4 despite receiving infliximab at a dose of 10 mg/kg every
8 weeks plus MTX, patients were switched to alternative
treatment options. Ongoing results show that these currently available therapies can be highly effective in patients with
early RA, when applied in the setting of tight disease control13,14,15. Notably, although combination therapies initially provided earlier clinical improvement and less joint damage progression, all 4 treatment strategies ultimately
achieved similar clinical improvements at 2 years16. The
authors also observed that combination therapy required
fewer treatment adjustments compared with initial
monotherapy, and could be withdrawn successfully. A subsequent study compared outcomes in patients from the BeSt
study who were treated to achieve a specified disease activity target (DAS ≤ 2.4) with those managed with routine care
in early arthritis clinics16. At baseline, patients from the
BeSt study had more advanced disease than those managed
with routine care, including longer median disease duration
(0.5 vs 0.4 yrs, respectively; p = 0.016), higher mean baseline DAS28 (6.1 vs 5.6; p < 0.001), more rheumatoid factor
(RF)-positive patients (66% vs 42%; p < 0.001), and more
patients with radiographic joint damage (71% vs 53%; p <
0.001). Despite having more advanced disease, BeSt
patients treated to achieve the target disease activity experienced greater improvements in functional ability scores
(+0.7 vs +0.5 points, respectively; p = 0.029), and a higher
remission rate (DAS28 < 2.6, 31% vs 18%; p < 0.005) compared with routine care in early RA clinics. Overall, the
results from the BeSt study illustrate how intensive monitoring of patients involving treatment to a predefined target
(in this case DAS remission) is beneficial to patients with
early RA. The study shows that initial treatment should be
aggressive, with early use of biologic therapy considered,
and that treatments should be altered quickly (either by dose
escalation or switching to alternative effective agents) if the
patient is not achieving the desired low level of disease
activity.
The TICORA (Tight Control of Rheumatoid Arthritis)
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Mease: Tight control of RA
1571
study compared an intensive management strategy with routine care in 111 patients with active RA17. Intensively managed patients saw a rheumatologist every month and those
who had not achieved a DAS ≤ 2.4 received a dose increase
or were switched to an alternative therapy. The study began
in 1999, before the introduction of biologic therapies. All
patients in the intensively managed group initially received
SSZ, the dose of which was increased if DAS ≤ 2.4 was not
achieved. If responses remained insufficient, further treatment options included the addition of MTX, folic acid, and
hydroxychloroquine. Patients in the routine care group saw
a rheumatologist every 3 months and were treated at the
physician’s discretion. During this 18-month study, the
mean improvement in DAS was significantly greater in the
intensive management group than in the routine care group
(–3.5 vs –1.9, respectively; p < 0.0001). Further, more
patients in the intensive management group had a good
response (decrease in DAS ≥ 1.2, 82% vs 44%; p < 0.0001)
or were in remission (DAS < 1.6, 65% vs 16%; p < 0.0001)
than patients receiving routine care. Although conducted
before the biologic therapies became a treatment option, the
TICORA study clearly illustrates the principle that intensive
management of patients using a predefined disease activity
target is superior to management that does not involve a routine assessment of disease activity.
Results of the open-label CAMERA (Computer Assisted
Management in Early Rheumatoid Arthritis) trial also support the contention that tight control is superior to conventional management in RA. In that study, intensive treatment
with MTX was compared with conventional MTX treatment
in patients with early RA18. Patients in the intensive treatment group attended the outpatient clinic every month and
their MTX dose was adjusted on the basis of predefined
response criteria [swollen joint count, tender joint count,
ESR, and visual analog scale (VAS) assessments of general
well-being and pain] using a computerized decision program. Patients in the conventional treatment group attended
clinic every 3 months and were treated according to standard practice. In the intensive treatment group, 50% of
patients achieved at least one period of remission during the
2-year trial compared with 37% of those receiving conventional treatment (p = 0.03). Efficacy was significantly
greater in the intensive group for almost all clinical variables, including morning stiffness (p = 0.009), ESR (p =
0.007), tender joint count (p < 0.001), swollen joint count
(p < 0.001), VAS general well-being (p < 0.001), and VAS
pain (p = 0.001).
Results of a recent study illustrate how intensive management of early RA can lead to very high rates of clinical
remission19. In this pilot study, 21 patients with early RA
were treated with an intensified COBRA regimen (SSZ,
MTX, and high-dose step-down prednisolone, intensified by
adding hydroxychloroquine and continued low-dose prednisolone) with the option to further intensify MTX treatment
after 8 or 21 weeks and to add infliximab therapy after 21
weeks19. After 40 weeks of treatment, an impressive 19/21
patients (90%) had achieved remission (DAS28 < 2.6).
Other recent data suggest that tight control may improve
longterm functional disability20 and reduce the need for
joint surgery among patients with RA treated with an
anti-tumor necrosis factor (TNF) agent21. Tanaka and
coworkers20 followed 2775 patients in an observational
cohort study for whom 3 years of data were available. A significant correlation was found between tight disease control
(DAS28 < 2.6) and functional disability score [using the
Japanese version of the Health Assessment Questionnaire
(HAQ)]; tight control was significantly associated with
improving functional capability. A second study in patients
receiving anti-TNF treatment for ≥ 1 year found that mean
DAS28 (including a measure of CRP levels) among patients
who did not require joint surgery (n = 70) was significantly
lower (p < 0.001) than among patients who required joint
surgery (n = 21)21. The authors concluded that tight disease
control was important in reducing the need for joint surgery
among patients receiving biologic therapy.
Together, the data discussed above support the hypothesis that tight disease control using a specified level of disease activity as a clinical target may improve outcomes for
patients with RA. One caveat is that the majority of these
studies assessed the use of nonbiologic therapies. The use of
biologics is widespread in the treatment of RA, and is occurring earlier in the treatment process. Further studies would
therefore be valuable to assess whether the same benefits are
apparent if a tight control strategy is applied to treatment
with biologics. Nonetheless, these results suggest that treating patients to specified targets improves clinical outcomes,
regardless of the treatment. It may be that the specific treatment administered is less important than the principle of an
intensive management strategy that includes regular monitoring of disease activity and adjustment of treatments as
needed. In order to integrate a tight control approach into
routine rheumatology practice, it is critical that there are
suitable validated assessments of disease activity, and relevant and realistic clinical targets.
Assessments for Standard Clinical Care
Measuring disease activity and remission. Although recent
advances in treatment have led to an increase in the proportion of patients reaching a state of remission22 there is no
“gold standard” measurement of disease activity and remission in RA4. Numerous pooled indices have been developed
to measure disease activity, each of which incorporates 3–10
different assessments23,24,25,26,27,28,29,30,31. This in turn
means that several definitions of remission, all using different criteria, have been developed. No one disease activity
index is consistently used, meaning that clinical trials
throughout the world assess remission using different definitions. The ACR core data set25,27 and the DAS23,30,32 are
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The Journal of Rheumatology 2010; 37:8; doi:10.3899/jrheum.091064
the most commonly used indices in clinical trials. The DAS
assesses tender joint count, swollen joint count, ESR (or
CRP, although this is less well validated than ESR24), and
the patient’s VAS estimate of general health; using a mathematical formula, the DAS score is calculated33. The ACR
core data set uses the same basic assessments as the DAS
(tender joint count, swollen joint count, and measurement of
ESR) plus physician’s and patient’s assessments of global
disease activity and patient evaluations of pain and physical
function25. In addition, the ACR core data set measures
change in disease activity, whereas the DAS measures current disease state or severity. The DAS is generally considered to have greater utility than the ACR core data set as it
can be used to determine whether a patient has achieved low
disease activity or remission. DAS28, a modification of the
DAS involving only a simple joint count, has also been
developed and is often used. Different definitions of remission in RA exist for each index; it is defined by DAS as a
score < 1.634, by DAS28 as a score < 2.623, and by ACR as
meeting a minimum of 5 ACR remission criteria for at least
2 consecutive months10.
Another major set of DAS-based response criteria were
developed by the European League Against Rheumatism
(EULAR). These criteria combine an assessment of the
change in disease activity from baseline with an analysis of
the DAS reached at followup; patients are classed as having
a good response, a moderate response, or no response34.
EULAR remission is often described as a Disease Activity
Score of < 1.635.
Simpler instruments have been developed from the complex assessment tools discussed above. Two DAS-based
instruments, the Simplified Disease Activity Index (SDAI)
and the Clinical Disease Activity Index (CDAI) (Tables 1
and 2)24,36 use a simplified system of grading joint swelling
and tenderness (28-joint count); further, the CDAI includes
no laboratory assessments (the SDAI measures CRP).
Cutoff points for SDAI and CDAI remission are defined as
≤ 3.3 and ≤ 2.8, respectively24. Initial validation of the
SDAI showed good correlation with the DAS28 (Table 1) in
both absolute scores and changes over time37. Correlation
between the CDAI and SDAI was found to be almost complete, and the CDAI appeared to correlate strongly with the
DAS2824. However, results of 2 recent studies suggest that
the classification of a patient as being in remission or not
depends on the instrument used to define remission38,39. The
studies assessed and categorized patients according to various disease activity indices, and demonstrated that a greater
proportion of patients were assessed to be in remission using
DAS28 disease activity criteria compared with using the
CDAI and SDAI. These results suggest that the CDAI and
SDAI may be more stringent assessment tools for classification of remission.
Patient questionnaires. Although patient questionnaires do
not provide an objective assessment of disease activity, they
do allow a global overview of patient functioning. Since
1980, the disease-specific HAQ has been used to assess
functioning and global disease status in patients with RA40.
The main advantage of the HAQ is that it can be completed
by the patient in 5–10 minutes. Its main limitations are a
somewhat complex scoring calculation and the need to use
a ruler to measure VAS scores4.
To make the HAQ easier to use in standard rheumatology
care, the multidimensional HAQ (MDHAQ) has been developed41. The MDHAQ employs fewer questions than the
HAQ; in addition, the VAS has been converted from a
10-cm line to 21 circles, making it easier to evaluate (Figure
Table 1. Elements of the Simplified Disease Activity Index (SDAI), the Clinical Disease Activity Index (CDAI), the Disease Activity Score (DAS), and the
28-joint DAS (DAS28)*24.
Elements
No. of swollen joints
No. of tender joints
Acute-phase reactants
Patient global health
Patient global disease activity
Evaluator global disease activity
Total index
SDAI
Simple count (0–28)
CDAI
Simple count (0–28)
Simple count (0–28)
Simple count (0–28)
CRP, mg/dl (0.1–10.0)
—
—
VAS, cm (0–10.0)
VAS, cm (0–10.0)
No immediate scoring
due to CRP; simple
calculation possible
(0.1–86.0)
—
VAS, cm (0–10.0)
VAS, cm (0–10.0)
Immediate scoring due
to CRP; simple
calculation possible
(0.1–76.0)
DAS
More extensive joint
counts (0–2.86)
Ritchie Index: graded
joint counts; square root
transformed (0–4.77)
ESR, log transformed
(0.23–1.51)**
VAS, mm (0–0.72)**
—
—
No immediate scoring
due to ESR; simple
calculator required
(0.23–9.87)
DAS28
Simple count, square
root transformed (0–1.48)
Simple count, square root
transformed (0–2.96)
ESR, log transformed
(0.49–3.22)**
VAS, mm (0–1.40)**
—
—
No immediate scoring
due to ESR; simple
calculator required
(0.49–9.07)
* Based on transformation and weighting of individual elements according to the formula of the respective index; assumed ranges are 2–100 mm/h for ESR,
and 0.1–10 mg/dl for CRP. Table reproduced with permission (Clin Exp Rheumatol 2005;23 Suppl 39:S100-8). ** The DAS and DAS28 formulae have also
been modified to include CRP instead of ESR, and to substitute the patient global health by a constant. These versions are less commonly used and not well
validated. CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; VAS: visual analog scale.
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Table 2. Cutoff levels for disease activity states36.
Scale
CDAI
SDAI
DAS28
Low
≤ 10
≤ 11
≤ 3.2
Disease Activity State
Moderate
High
> 10 and ≤ 22
> 11 and ≤ 26
> 3.2 and ≤ 5.1
> 22
> 26
> 5.1
Remission
< 2.8
< 3.3
< 2.6
CDAI: Clinical Disease Activity Index; DAS28: 28-joint Disease Activity Score; SDAI: Simplified Disease
Activity Index.
Figure 1. Comparison of visual scales used to assess pain. MDHAQ: Multidimensional Health Assessment Questionnaire. From Best Pract Res Clin
Rheumatol 2007;21:755-87, with permission.
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1574
The Journal of Rheumatology 2010; 37:8; doi:10.3899/jrheum.091064
1). The form takes substantially less time for the physician
to assess and score compared with the HAQ. If more rapid
assessment is required, physical function, pain, and global
status scores can be registered at a glance and formally
scored in about 10 seconds into a composite index known as
the Rheumatology Assessment Patient Index Data
(RAPID)-341. RAPID-3 can be expanded by adding the
Rheumatoid Arthritis Disease Activity Index self-report
(RAPID-4) and the physician/assessor global estimate
(RAPID-5) templates that are included in the MDHAQ
forms. These forms and instructions for their use can be
downloaded from www.mdhaq.org.
Do We Have the Tools to Achieve Tight RA Control in
Routine Clinical Practice?
As treatment for RA improves, remission becomes an
important and more achievable goal, and so it is essential
that clinicians are able to accurately measure low levels of
disease activity. Validated tools are now available for evaluating a range of clinical variables in patients with RA, but
definitions of remission are not always standardized.
Several different definitions of remission are currently used,
and so variation in remission rates between clinical trials
may be due to the indices used, rather than the treatments
received. Indeed, a recent study in which patients’ disease
activity was assessed by different indices (including
DAS28, SDAI, and CDAI) demonstrated that different proportions of patients were found to be in remission depending on the definition used42; further comparisons of disease
activity indices are therefore required. A collaborative committee between ACR and EULAR has been convened to
develop a strict definition of remission that correlates with
very low or no disease activity22.
The case study below illustrates that routine disease
assessment, using a simplified tool such as the CDAI, could
provide valuable guidance when selecting initial therapy,
and an indication of when treatment intensification or a
switch in medication is required.
Case Study
A 42-year-old woman presented with a 12-month history of
RA. Her primary care physician prescribed ibuprofen and
prednisone, and referred her to a consultant rheumatologist.
Her first rheumatologist initiated MTX 3 months after diagnosis and her symptoms initially improved before worsening. She decided to transfer her care as the rheumatologist
was reluctant to initiate biologic therapy.
At presentation, her symptoms included morning stiffness (lasting 1 hour), polyarticular pain, fatigue, and difficulty with her work as a receptionist. The medication on
presentation included MTX 20 mg/week, folic acid 1
mg/day, prednisone 5 mg/day, and ibuprofen 800 mg 3 times
daily. Her baseline characteristics are shown in Table 3.
Hand radiographs showed erosions at both second metacar-
pophalangeal (MCP) joints. With a CDAI of 23, she was
considered to have high disease activity24 (Tables 2 and 3),
while her SDAI and DAS28 indicated moderate disease
activity (Tables 2 and 3). She was considered a suitable candidate for TNF inhibitor therapy and agreed to this course of
treatment.
Following a negative tuberculosis skin test, etanercept 50
mg/week was initiated. The tight control model of optimal
care was agreed upon, and treatment was temporarily
increased to MTX 25 mg/week and prednisone 10 mg/day,
while awaiting the full effect of etanercept therapy. CDAI
was the principal assessment tool, with a treatment goal of
low disease activity; SDAI and DAS28 were calculated
when CRP levels were available.
Disease control during Years 1 and 2 are summarized in
Table 3. After 1 month, the patient had low to moderate disease activity and the treatment regimen was continued. After
2 months, she was considered to have low disease activity
and MTX was reduced to 20 mg/week and prednisone to 5
mg/day. After 3 months, disease activity scores were
unchanged and the treatment regimen was maintained at this
level. She continued to exhibit low disease activity over the
following 2 years and prednisone was discontinued altogether after 6 months.
Treatment modification on loss of disease control. Two
years after starting etanercept, she began to experience
increased RA symptoms (Table 3) and fatigue. She had elevated liver function tests and radiographic evidence of one
new erosion in her third left MCP joint. Prednisone was temporarily reintroduced at 20 mg/day, and tapered over 1
month. MTX was not increased because of the liver test
abnormalities. At the 1-month followup visit, disease activity remained high, despite the higher prednisone dose.
Considering the next course of action, the results of the
study by Finckh and coworkers44 were taken into account.
That study suggests that on failure of a TNF inhibitor, switching to an agent with a different mechanism of action, such as
B cell depletion, may be more effective in regaining disease
control than an alternative TNF inhibitor. Therefore, rituximab was initiated (2 times 1000 mg infusions separated by 2
weeks), along with prednisone 10 mg/day and MTX 12.5
mg/week. One month later, the patient had low to moderate
disease activity (Table 3) and at the 3-month followup visit,
her CDAI was 8, indicating low disease activity. Liver tests
had normalized and prednisone was decreased to 5 mg/day.
She continues to be seen in the clinic every 2 months.
Her CDAI score remains low, suggesting good disease control, and her overall global and functional status remains
good. Repeat hand radiographs 1 year after initiation of rituximab showed no new erosions. Based on recent data suggesting optimal disease control with fixed retreatment
schedules and several trials suggesting 6-month intervals45,46,47,48,49, she is receiving repeat courses of rituximab
at this interval.
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Table 3. Disease control over time in the patient described in the case study.
Outcome
Baseline
Joints
Swollen
4
Tender
7
Global assessment
Patient
6
Physician
5
CDAI
23
Laboratory values
CRP, mg/dl
1.5
RF, units
128
CCP, units
85
SDAI
24.5
DAS28
4.94
Month 1
Etanercept
Month 2
Year 2
—
—
0
2
6
10
0.8
13.8
3.77
4
3
13
2
1
5
Rituximab
Month 1
Month 2
2
3
1
2
0.6
6
5
27
1.2
4
3
12
3
2
8
—
0.8
5.6
2.73
28.5
5.18
—
—
8.8
3.24
CDAI: Clinical Disease Activity Index; CRP: C-reactive protein; DAS28: 28-joint Disease Activity Score;
RF: rheumatoid factor; SDAI: Simplified Disease Activity Index; CCP: citric citrullinated peptide antibody.
For this patient, TNF inhibition was initiated with the
aim of achieving tight disease control. Low disease activity,
measured using the CDAI, SDAI, and DAS28, was the clinical target. An increase in disease activity prompted reevaluation of treatment and a switch to an alternative biologic
agent to regain tight disease control.
Conclusions
The concept of tight control — intensive disease management based on specific clinical variables — is well accepted
in the management of many chronic conditions and has
improved patient outcomes. In patients with RA, there is
currently no gold standard for assessing disease activity and
outcomes, so patients may not receive optimal treatment
over time. Studies have shown that tight control and intensive treatment can significantly improve outcomes compared with standard approaches in RA, regardless of the
treatment received. It remains to be seen whether tight control can not only control disease activity and reduce radiographic progression, but also reduce the increased risk of
early cardiovascular morbidity and mortality due to inflammation-induced atherogenesis, an important comorbidity of
RA. Nonetheless, the weight of evidence from well
designed controlled clinical trials indicates that the principles of tight disease control should now be applied by all
physicians in routine clinical practice. The overriding principle of the tight control approach is not the choice of individual therapies but rather the regular monitoring of patients
and early switching or adjustment of therapies that fail to
adequately control disease activity. On a practical note, the
implementation of tight control into routine care will require
quick and simple validated tools for defining treatment targets and monitoring disease activity. Tools such as the
CDAI and RAPID-3 appear to meet these requirements; in
addition, the CDAI appears not only to provide simplicity
but also, as recent studies suggest38,39, to be a more stringent
tool for assessing remission. However, further studies are
still needed to define the most appropriate assessment tools
for assessing remission in routine clinical practice, as well
as appropriate and achievable clinical targets reflecting tight
disease control. Ultimately, the use of tight control should
lead to treatment optimization and will provide the best
chances of improvement and remission for patients with
RA.
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